Transmembrane receptor tyrosine kinases (RTKs) comprise a large and evolutionarily conserved family of structurally related proteins capable of transducing extracellular signals to the cytoplasm. The latent oncogenic potential of these molecules and the molecular mechanisms by which they function in signalling pathways have been the subject of extensive study.
In addition, genetic and biochemical analyses of a variety of developmental mutants have led to recognition of the pivotal roles played by RTK-mediated signalling pathways in the regulation of cell determination, migration, and proliferation. Notable examples in Drosophila include the role of sevenless and its ligand, bride of sevenless, in R7 photoreceptor determination (Kramer, H., Cagan, R. L. & Zipursky, S. L. (1991), Nature, 352, 207-212), and of DER/flb in early morphogenetic events during gastrulation (Schejter, E. D. & Shilo, B.-Z. (1989), Cell, 56, 1093-1104). Similarly, in the mouse, loss of function mutations at the W/c-kit (Geissler, E. N., Rayn, M. A. & Housman, D. E. (1988), Cell, 55, 185-192; Chabot, B., Stephenson, D. A., Chapman, V. M., Besmer, P. & Bernstein, A. (1988), Nature, 335, 88-89) and Sl (Russell, E. S. (1979), Adv.Genet., 20, 357-459) loci have revealed the importance of the Kit receptor and its ligand in melanogenesis, hematopoiesis, and gametogenesis (Dubreuil, P., Rottapel, R., Reith, A. D., Forrester, L. & Bernstein, A. (1990), Ann. N.Y. Acad. Sci., 599, 58-65; Williams, D. E., Eisenman, J., Baird, A., Rauch, C., Ness, K. V., March, C. J., Park, L. S., Martin, U., Mochizuki, D. Y., Boswell, H. S., Burgess, G. S., Cosman, D. & Lyman, S. D. (1990), Cell, 63, 167-174; Copeland, N. G., Gilbert, D. J., Cho, B. C., Donovan, P. J., Jenkins, N. A., Cosman, D. Anderson, D., Lyman, S. D. & Williams, D. E. (1990), Cell, 63, 175-183 and Flanagan, J. G. & Leder, P. (1990), Cell, 63, 185-194) while a deletion in the gene encoding PDGFR-.alpha. has been correlated with the Patch mutation, which also causes a defect in melanogenesis (Stephenson, D. A., Mercola, M., Anderson, E., Wang, C., Stiles, C. D., Bowen-Pope, D. F. & Chapman, V. M. (1991), Proc.Natl.Acad.Sci., 88, 6-10). These observations, together with others (reviewed in Pawson, T. & Bernstein, A. (1991), Trends Gen., 6, 350-356), have established the importance of receptor-ligand interactions in the regulation of development.
Angiogenesis in both the embryo and adult requires the differentiation, proliferation, and migration of endothelial cells. Tissue transplantation studies with quail/chick chimeras have established that the developmental cues for both endothelial cell differentiation and proper patterning of vessels are extracellular and not pre-programmed within the cell (Noden, D. M. (1988) Development, 103, 121-140) Several peptide hormones, such as bFGF, VEGF and PD-EGF, have been shown to have both mitogenic and chemotactic effects on cultured endothelial cells (see Tomasi, V., Manica, F. & Spisni, E. (1990), BioFactors, 2, 213-217; Klagsbrun, M. & D'Amore, P. (1991), Annu.Rev.Physiol., 53, 217-239, for reviews). However, many of these factors also show similar effects on other cell types, implying that receptors for these factors are also expressed by such cells.
Studies have demonstrated that both tyrosine kinase activity and phosphotyrosine-containing proteins are increased in embryonic chicken heart relative to the adult (Maher, P. A. (1991). J.Cell Biol., 112, 955-963), and that inhibitors of kinase activity impede inductive processes during in vitro differentiation of cardiac explants derived from chicken embryos (Runyan, R. B., Potts, J. D., Sharma, R. V., Loeber, C. P., Chiang, J. J. & Bhalla, R. C. (1990), Cell Reg., 1, 301-313).